Is JPH2 p.Asp454fs (c.1359dup) pathogenic?

JPH2 p.Asp454fs (c.1359dup) is classified Uncertain significance in JPH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-04). Very rare (popmax 0.000175%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with JPH2 p.Asp454fs (c.1359dup)?

JPH2 p.Asp454fs (c.1359dup) is associated with Cardiovascular phenotype (ClinVar).

How common is JPH2 p.Asp454fs (c.1359dup) in the general population?

JPH2 p.Asp454fs (c.1359dup) is very rare (popmax 0.000175%, nfe) (gnomAD).

JPH2 p.Asp454fs

c.1359dup · VCV3862295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2	GERP -0.21, phastCons 0.33

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000175% European (non-Finnish) · 2/1,145,932 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000194% 3/1,543,508 alleles · very rare exomes 3/1,391,296 · genomes 0/152,212 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0018%	55,524
European (non-Finnish)grpmax	0.000175%	572,967

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: JPH2
Protein: p.Asp454fs
Coding: c.1359dup
MANE Select: NM_020433
Type: Duplication
Location: chr20:44116315 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.09 · 2 PDB
Residue 454: the 'disordered' region; a UniProt-annotated variant site (in cmd2e; uncertain significance)

Full JPH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

JPH2 p.Asp454Asn Uncertain significance ★ ⚠ same residue
JPH2 p.Asp454Ala Uncertain significance ★★ ⚠ same residue
JPH2 p.Ser171_Asn172dup Uncertain significance ★★ same condition
JPH2 p.Asp454_Pro463del Uncertain significance ★ same residue
JPH2 p.Gly199_Phe200insGly Uncertain significance ★ same condition
JPH2 p.His567fs Uncertain significance ★ same condition
JPH2 p.Thr288fs Uncertain significance ★ same condition
JPH2 c.-4T>A Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/jph2-p-asp454fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown